WO2004088564A1 - Molecular function network display method - Google Patents

Abstract

There are provided: a graphical user interface for generating a molecular function network of an arbitrary range according to specification by a user and displaying the molecular function network in graphics; and a graphical user interface including a molecular network window for displaying a molecular network contained in the molecular function network and an information window for displaying at least one information selected from a group consisting of a molecule, a molecule pair, and a biological event contained in the molecular function network, and characterized in that operation is performed by interlocking items associated in the molecular network window and the information window. It is possible to freely process and display a molecular function network containing biological event information including a sickness event by using a computer.

Description

 Description Method for displaying molecular function networks

 This effort belongs to the field of biological information processing, and in particular relates to a graphical user interface, programs, devices and media for displaying and manipulating information on biomolecules and their biological functions, phenomena and diseases in living organisms. . Background art

In living organisms, there are various molecules such as amino acids, peptides, fats, carbohydrates, and low molecular compounds in addition to biopolymers such as nucleic acids and proteins. These biomolecules function by having specific relationships such as binding, competition, interaction, and enzymatic reaction with other molecules in vivo. In addition, molecules that are ingested from outside the body, such as drug molecules and nutrients, have a specific relationship with the biomolecules, thereby affecting or affecting the functions of the living body. Such a relationship between molecules in a living body can be represented as a graph in which a molecule is a vertex and the related molecule is connected by an edge. Such a graph expressing the relationship between molecules is hereinafter referred to as a “molecular network”. Adds information about the functions of the molecules in the living body to the molecular network and information about the phenomenon in the living body caused by the involvement of the molecules in the living body (hereinafter referred to as “biological events”). Thus, it is possible to express the mechanism of the molecular level of a living body. In addition, a disease can be regarded as a state in which certain biological events are extremely enhanced or suppressed, and information on biological events that are changing in the disease (hereinafter referred to as “pathological events”) is added to a molecular network. Thus, a molecular mechanism of a disease can be expressed. Such a molecular network to which information on the function of molecules and information on biological events (including pathological events) are added is hereinafter referred to as “molecular function network”. molecule The method of generating and processing a functional network by a computer is described in PC / JPO / 07830 / PCT / JP03 / 0284/47.

 The method of displaying molecular networks has been done by drawing a certain range of molecular networks as a diagram that is appropriately arranged so that the molecules in them do not overlap. The molecular network can be drawn manually by humans, or it can be drawn and displayed by a computer. Examples of methods for drawing a molecular network using a computer include KEGG, EcoCyc, GeNet, etc., but these methods cannot freely display a molecular function network including information on the function of molecules and information on biological events. . In addition, PCT JP 01 0 0 7830 and PCTZ JP 0 3/0 284 7 also show a method of generating and processing a molecular function network as a data structure, It does not disclose a method of freely displaying the graphics. Disclosure of the invention

 An object of the present invention is to provide a method and a system for freely processing and displaying a molecular function network including information on a biological event using a computer. More specifically, an arbitrary range of molecular function networks can be generated according to the user's instructions and displayed as graphics, allowing users to easily examine the relationship between biological event information and molecular networks. It is an issue of the present invention to provide means for

 Biological events may be related to each other, and it is also an object of the present invention to provide a means for allowing a user to easily check such a relationship. Furthermore, there is a means to enable users to easily examine not only molecular functional networks consisting of biomolecules, but also molecular functional networks that include drug molecules, molecules derived from outside the body, and biomolecules of different species. Provision is also an object of the present invention.

The present inventors have worked diligently to solve the above problems, and as a result, responded to user instructions. Means for generating a molecular function network in an arbitrary range, a means for displaying the molecular function network in a graphic form, and a method in which a user designates an arbitrary element in the displayed molecular function network to specify the molecular function network. We have found that the above problems can be solved by combining the means for generating a function network and displaying graphics.

 According to the present invention, there is provided a graphical user interface for generating a molecular function network in an arbitrary range in accordance with a user's instruction and displaying the molecular function network in a graphic form. Further, according to the present invention, a molecular network window for displaying a molecular network included in the molecular function network, and one or more information selected from the group consisting of a molecule, a molecule pair, and a biological event included in the molecular function network are displayed. There is also provided a graphical user interface that includes an information window that operates in conjunction with the molecular network window and related items in the information window.

 According to a preferred embodiment of the present invention, the following invention is provided.

Molecular pairs in the molecular network window and biological events that occur due to quantitative and / or qualitative changes in the molecular pairs or that cause quantitative and Z or qualitative changes in the molecular pairs A graphical user interface for displaying the information of each other in association with each other and operating the display items in conjunction with each other;

Information on the molecule in the molecular network window and the information on the biological event that occurs due to the quantitative and / or qualitative variation of the molecule or that causes the quantitative and / or qualitative variation of the molecule. A graphical user interface for displaying the items in association with each other and operating the displayed items in conjunction with each other;

A graphical user interface for displaying a molecule in a molecule network window and information on a drug / bioactive molecule acting on the molecule in association with each other, and operating the displayed items in conjunction with each other;

A window that displays the list of molecules in the molecule network window is provided, and the molecules in the molecule network can be operated in conjunction with the items in the list window. A graphical user interface characterized by:

It has a window that displays a list of information about molecules and / or molecule pairs in the molecule network window, and operates in conjunction with the molecules and / or molecule pairs in the molecule network and the items in the list window. Graphical user interface;

A graphical user interface as described above, characterized by displaying information on molecules and / or molecule pairs in a categorized or hierarchical manner;

A window is provided for displaying a list of biological pathways to which the molecules and / or molecule pairs in the molecule network window belong, and the molecules and z or the molecule pairs in the molecule network are linked with the items in the list window. Graphic user interface characterized by operation;

A graphical user interface as described above, characterized in that the biological pathways are displayed in a categorized or hierarchical manner;

A window is provided for displaying a list of information on biological events related to molecules and / or molecule pairs in the molecule network window, and the molecules and / or molecule pairs in the molecule network are linked to the items in the list window. Graphical user interface characterized by operation;

The above graphical user interface, wherein the biological events are displayed in a hierarchical manner;

The above graphical user interface using Gene Ontology as a layered biological event;

A graphical user interface having a window for displaying a list of information on pathological events, wherein the related items are operated in conjunction with each other in the list window;

The graphical user interface as described above, wherein the disease state events are displayed by category;

The graphical user as described above, wherein the pathological events are displayed in a hierarchical manner. Interface;

A graphical user interface as described above, containing a list of information on quantitative and / or qualitative changes in biomolecules associated with the pathological event;

A graphical user interface wherein a keyword search is performed on the information of the molecular function network, and the items hit by the search are highlighted and displayed in a molecular network window and / or a related list window; A graphical user characterized in that one or more molecules and / or molecule pairs are selected, the molecule and the molecule or the molecule pair are designated as end points, and a molecular function network is generated and displayed by a connect search. INTERFACE Ace;

A method for displaying a molecular function network, wherein a molecule and / or a molecule pair is distinguished and displayed by a symbol and / or a color type based on information on a modification state and / or an activation state;

A method for displaying a molecule-function network, wherein a molecule and / or a molecule pair is distinguished and displayed by a symbol and z or a color type based on information of a biological event; a biomolecule to be acted on by a bioactive molecule A method for displaying a molecular function network, wherein a molecule and / or a molecule pair is distinguished and displayed by a symbol and / or a color based on the information of

A molecular function network characterized by distinguishing molecules and / or molecule pairs by symbol and / or color type based on numerical information indicating the quantitative and / or qualitative state of molecules and / or molecule pairs. Display method;

The method for displaying a molecular function network as described above, wherein numerical information obtained by an experimental method of any one of DNA microarray, proteomitas, and metaporomitas is used;

A method for displaying a molecular function network as described above, characterized in that numerical information on mRNA or protein of different species is associated based on the ortholog relation; a molecular pair is connected by a drawing method based on the information on the association of molecular pairs. Table with distinct sides A method for displaying a molecular function network characterized by showing;

 When displaying a complex composed of two or more biomolecules, it is possible to switch between displaying a single symbol representing the complex or displaying multiple symbols representing each constituent molecule. A method of displaying a characteristic molecular function network; a biological event relating to a molecule and / or a molecule pair in the molecular network is displayed as a vertex, and the molecule and / or the molecule pair and the vertex are connected by an edge. Displaying a molecular function network characterized by displaying;

A bioactive molecule that targets a molecule and / or a molecule pair in a molecular network as a target of action is displayed as a vertex, and the molecule and / or molecule pair and the vertex are connected by an edge to be displayed. How to display molecular function networks

Display the biological pathway and Z or other molecular network related to the molecule and Z or the molecule pair in the molecular network as a vertex, and display the molecule and Z or the molecule pair and the vertex by connecting the edge with the edge. A method for displaying a molecular function network, characterized by:

 A method for displaying a molecular functional network, wherein a molecular network from two or more end points to a common upstream molecule or a common downstream molecule is generated by a connect search, and the common upstream molecule or the common downstream molecule is marked and displayed. ;

 —Specify one or more molecules in the generated molecular network, perform a connect search again, and mark and display the partial molecular network generated in the original network;

A display program for a molecular function network that executes the graphical user interface or display method according to any of the above;

A display program for a molecular function network that executes the above display method;

A computer-readable medium storing the above program; and

A display device for a molecular function network capable of executing the above program. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a diagram showing a display example of a graphical user interface of the present invention.

 FIG. 2 is a diagram showing an example in which a complex is expanded and displayed.

 FIG. 3 is a diagram showing an example in which molecules are distinguished and displayed according to a modification state and / or an activation state.

 FIG. 4 is a diagram showing an example in which sides connecting molecules are distinguished and displayed according to the relationship between the molecules.

 FIG. 5 is a diagram showing an example in which a biological event and a passway are added to a molecular network and displayed. Biological events include “mucus secretion” and “bronchoconstriction” connected by thick arrows, and “arachidonic acid cascade” connected by thick arrows are pathways.

 FIG. 6 is a diagram showing an example in which the items of the molecule pairs in the molecule network window and the information window are displayed in association with each other.

 FIG. 7 is a diagram showing an example in which the items of the pathological event in the molecular network window and the information window are displayed in association with each other.

 FIG. 8 is a diagram showing an example in which items of drug molecule information in the molecule network window and the information window are displayed in association with each other.

 FIG. 9 is a diagram showing a display example of a molecular network for controlling the expression of a protein by a transcription factor, using a partitioning graph.

 FIG. 10 is a diagram showing an example of extending a molecular network by performing a connect search by designating one molecule in the molecular network as a starting point. .

 FIG. 11 is a diagram showing an example of searching for a common upstream molecule from two molecules and marking and displaying the common upstream molecule in a molecular network. The molecule used as the starting point of the search is marked with *, and the common upstream molecule is marked with #.

Fig. 12 shows a partial network obtained by specifying a molecule to be the starting point and a molecule to be the ending point in the molecular network once generated, and performing a connect search again between them. FIG. 8 is a diagram showing an example in which a mark is displayed.

 FIG. 13 is a diagram showing a display example of a graphical user interface for operating the molecular network in association with information on a pathological event expressed in a hierarchical manner.

 FIG. 14 is a diagram showing a display example of a graphical user interface for operating a molecular network in conjunction with Gene Ontology, which is information on biological events represented in a hierarchical manner.

 -Figure 15 shows the concept of linking molecular networks with various biological and related information. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, embodiments of the present invention will be specifically described with reference to the drawings as appropriate, but the scope of the present invention is not limited thereto.

 The meanings or definitions of the terms in this specification are as follows.

 “Organism” is a concept that includes, for example, organelles, cells, tissues, organs, and living organisms. In addition, living organisms such as bacteria, viruses, and prions that are parasitic on living organisms are also included in the concept of living organisms.

 “Biological event” is a concept that includes all phenomena, responses, reactions, and symptoms that occur endogenously or exogenously in a living body. Specific examples include transcription, cell migration, cell adhesion, cell division, neural circuit excitation, vasoconstriction, increased blood pressure, hypoglycemia, fever, convulsions, infection by foreign organisms and parasites such as viruses, and the like. it can. In addition, the response to a physical stimulus from outside the living body such as light or heat can be included in the concept of a living event.

The “pathological event” is a concept included in the “biological event”, and refers to a state in which the “biological event” can be determined to be a disease or pathological condition as a result of an increase, decrease, or qualitative change in the “biological event”. For example, “pathological events” as a result of abnormally increasing “biological events” of increased blood pressure may include hypertension or hypertension, and blood glucose may fall within a normal range. A “pathological event” that exceeds the result may include hyperglycemia or diabetes. In addition, not only events related to a single biological event as in the above example, but also pathological events related to multiple types of biological events. Furthermore, in the present invention, information related to diseases such as disease names, symptoms / symptoms, clinical test items, disease classification, and complications can be treated as information on pathological events in a broad sense in the present invention.

 “Molecule” includes nucleic acids, proteins, lipids, carbohydrates, organic compounds, inorganic compounds, metal ions, and the like, which are present in living organisms. The “molecules” of the present invention also include molecules such as drug molecules, nutrients, environmental pollutants, and toxic substances that exist or are taken in vitro. The term “biomolecule” includes molecules that are naturally present in living organisms, as well as molecules originally possessed by foreign organisms such as viruses or bacteria. “Bioactive molecule” means a molecule having one or more physiological activities, and is used as a concept including an is drug.

 “Association” means indicating or recording a direct or indirect association between two or more data items selected from molecules, subnets, biological events, pathological events, and genes. “Association information” means information recorded by “association”. A “molecule pair” refers to a collection of two or more associated molecules. The method of performing a connect search using a molecule and / or a molecule pair as an end point is described in detail in, for example, the specification of PCT / JP01 / 07830 or PCT / JP03 / 0284847. It is described in.

“Biological pathway” refers to a range of molecular networks called by name. Hereinafter, it may be simply referred to as “pass path”. Examples of pathways include glycolysis, the citrate cycle, the MAP kinase cascade, and the Caspase cascade.However, it is convenient to name any arbitrary range of molecular networks and treat them as pathways. It goes without saying that you can do it. FIG. 1 shows a display example of a graphical user interface according to the embodiment of the present invention. The graphical user interface of the present embodiment includes a molecular network window displaying a molecular network included in the molecular function network, a molecule, a molecule pair included in the molecular function network, and a biological event pathology. At least one selected from the group consisting of a biological event and a biological event and / or a pathological event included in the biological event. And an information window to be displayed.

 The data of the molecular function network targeted in the present embodiment is prepared by the method described in, for example, the specification of PC TZ JP 01/07830 or PCT / JP 03/02847. can do. According to the method described in the specification, it is possible to generate data of an arbitrary range of molecular functional networks including an arbitrary molecule, a biological event or a pathological event specified by a user. Further, as another embodiment, for example, data expressing information of a molecular function network described in a literature or a review by an appropriate encoding method may be used.

 The molecular network window and the information window may be displayed as independent windows as shown in FIG. 1, or may be displayed such that one window is included in the other window. Also, a plurality of molecular network windows and information windows may be displayed simultaneously. For example, one information window can display detailed information, and the other information window can display only summary information such as titles and abbreviations of display items. As yet another embodiment, one information window may be displayed for a plurality of molecular network windows.

 In the molecule network window, molecules can be displayed as vertices (the vertices are sometimes called “nodes”), and the molecule network can be displayed as a graph that connects related molecules with edges. The vertices representing a molecule can be represented by symbols according to the type of molecule, for example, an ellipse for a protein and a rectangle for a small molecule. The term vertex does not mean only one point, but must be interpreted in a broad sense, including areas with areas.

 When a plurality of molecules form a complex and function as one, the complex is

It may be displayed as one vertex like one molecule. In this case, it is preferable to display the complex with another symbol indicating that the complex is used. Fig. 2 As shown, the molecules constituting the complex may be expanded and displayed in the symbol representing the complex. One of the preferred embodiments of the graphical user interface of the present invention is that the user can switch between the display method in which the complex is not expanded and the expanded display method as required. The expression of the complex when expanded is not limited to that shown in Fig. 2, and it goes without saying that any expression may be used as long as the components of the complex can be distinguished.

 For a molecule whose relationship with other molecules in the molecular network changes due to modification such as phosphorylation, the molecular network may be represented by placing a separate vertex for each modification state of the molecule. In addition, for a molecule whose relationship with another molecule changes due to a difference in the active or inactive state, a separate network may be set for each difference in the activation state of the molecule to represent a molecular network. In this case, at the position of the vertex, a symbol representing the molecule and a symbol representing the modification state and / or activation state as shown in Fig. 3 shall be displayed, or the modification state and / or activation state shall be indicated. Different types of symbols may be displayed depending on the status so that the modified status and / or the activated status can be distinguished. Fig. 3 is an example of symbols, and it goes without saying that any symbol may be used as long as the user can easily recognize the difference between the modification state and / or the activation state of the molecule. No.

 As one of preferred embodiments of the present invention, a molecule and / or a molecule pair is represented by a symbol and Z or a color based on numerical information indicating the quantitative and Z or qualitative state of the molecule and / or the molecule pair. A method for displaying a molecular network to be displayed in a distinguished manner is provided. Examples of such numerical information include data on the amount of mRNA measured in experiments using a DNA microarray (also called a DNA chip), data on the amount of protein measured in a proteomics experiment, and metabolism measured in a metaporome experiment. Data on the amount of products (mainly low molecular substances) can be cited. Not only the absolute value of the substance abundance but also the value of the ratio of the substance abundance between two or more different states (eg, different cells or organs) can be used as numerical data.

If the above numerical information relates to the amount of mRNA, it is coded by mRNA. The molecules in the molecular network corresponding to the protein to be displayed may be displayed in different colors. As a method other than color coding, the size and type of a symbol representing a molecule in a molecular network may be changed based on numerical information. If the mRNA or protein to be measured is derived from a different species than the proteins in the molecular network, the mRNA or protein to be measured is determined based on ortholog information on the correspondence between the species and the proteins. It is also possible to specify a protein corresponding to in a molecular network and color the protein based on numerical information. Such a method of displaying molecules in a molecular network based on numerical information is useful for users to interpret experimental data in light of the molecular network.

 The way of drawing (drawing method) between the related molecules (that is, the molecule pair) may be changed according to the relationship between the molecules. For example, as shown in Fig. 4, the relationship between binding between molecules is indicated by a solid line arrow, the relationship between an inhibitory molecule and its target molecule is indicated by an arrow with a horizontal bar, and the relationship between a transcription factor and a transcriptionally regulated protein. Can be represented by dotted arrows, and the relationship between substrates, products, and catalyzing enzymes involved in the enzyme reaction can be represented by branched arrows. The direction of the arrow should be determined according to the direction of signal transmission, but if the direction cannot be determined, a pure line without an arrow may be drawn. The thickness and color classification of the line may be changed according to the power of expression and the relationship between the molecules according to the type of the line.

 By changing the way of drawing the edges between molecules according to the relationship between molecules as described above, as shown in FIGS. 1, 5, and 8, signal transduction, enzymatic reaction, transcription factor This makes it possible to display a molecular network including relationships between different types of molecules, such as regulation of protein expression by the user, in a form that is easy for the user to understand. In addition, as shown in Figs. 5 and 8, the relationship between proteins (indicated by ellipses) and the conversion (metabolism) of enzymatic reactions of small molecules (indicated by rectangles) are shown. Relationships can be displayed together in a single molecular network. As described above, displaying the molecular network including the relationship between different types of molecules by changing the way of drawing the sides between the molecules according to the relationship between the molecules is one of the preferred embodiments of the present invention. It is.

Depending on the type of relationship between molecules, whether or not to connect molecules during connect search is controlled. Controlling to generate and display different molecular networks is also one of the preferred embodiments of the present invention. For example, by using only the relationship of an enzyme reaction as a relationship between molecules in a connection search, a molecular network consisting of only an enzyme reaction such as a metabolic system or a kinase cascade can be generated and displayed. In addition, by using only the relationship between a transcription factor and a protein whose transcription is regulated as a relationship between molecules in a connect search, a molecular network for protein transcription regulation can be generated and displayed. Examples of such types of relationships between molecules include enzymatic reactions, activation, inactivation, inhibition, binding, protein expression induction, protein expression suppression, and the like. The method of dividing the type of the relationship between molecules is not limited to these, and it goes without saying that the relationship between two or more types of molecules may be used.

 The position of each molecule (vertex) constituting the molecular network may be determined interactively by a user using an input device such as a mouse, but more preferably, if the symbol representing each molecule is as large as possible. It may be determined by calculation so as to obtain an optimal arrangement. As a computational algorithm for this purpose, for example, a method such as Force Directed Method or Layer Drawings fe (GD Battista et al., Graph Drawing -Algoritnms for the Visualization of Graphs, Chapter 9 & 10, Prentice Hall, 1999) is used. be able to.

 When a molecular network including a large number of molecules is generated by the connect search, the graph of the molecular network may be too complicated to be easily understood by the user only with the above-described optimal arrangement method. In such a case, the molecular network may be displayed as a “partitioning graph” by the following method. This method is characterized in that a graph of one molecular network is divided into a plurality of regions (hereinafter, referred to as "partitions"), and is rendered so that nodes belonging to each partition are optimally arranged. .

Nodes that are directly connected to a certain node in the graph of the molecular network are hereinafter referred to as “adjacent nodes”. Among the nodes in the molecular network, a node having a certain number of adjacent nodes is a node at the center of the partition (hereinafter, “central node”). Do ”). A partition is composed of a central node and adjacent nodes connected to it. After determining multiple partitions for the entire molecular network, the central node of each partition is located at the optimal position. For this purpose, the above-mentioned calculation algorithm ゃ simulated annealing method can be used.

 After the provisional arrangement of the central node is determined in this way, the adjacent nodes are optimally arranged for each partition. Finally, the arrangement of the central node and adjacent nodes of each partition is readjusted while avoiding collisions between molecules belonging to different partitions. For this purpose, for example, the Force Transfer method can be used. Fig. 9 shows a display example of the partitioning graph whose layout is determined in this way.

As one embodiment of the present invention, coordinates representing the arrangement of each node of the molecular network graph displayed in the molecular network window are stored in a file so that the arrangement of the molecular network can be reproduced when the user desires. A method is provided for doing so. In another embodiment, a list of molecules (corresponding to the nodes of the graph) and molecule pairs (corresponding to the edges of the graph) constituting the graph of the molecular network is saved in a file, and the connect search is performed when the user desires. Methods are also provided that allow the molecular network to be reproduced without re-execution. In addition, by combining these two methods, it is possible to easily reproduce the molecular network once generated and displayed by the user, including the arrangement when the user desires. A graphical user interface for performing these methods is also an embodiment of the present invention. As one embodiment of the present invention, a molecular network is generated by selecting one or more molecules and / or molecule pairs in a molecule network window, designating the molecules and / or molecule pairs as end points, and performing a connect search. A graphical user interface is provided, wherein the graphical user interface is displayed. In this case, the molecular network generated by the connect search may be displayed in a new molecular network window, or may be displayed in addition to the original molecular network. By adding to the original molecular network, users can expand the molecular network interactively and easily. Zhang can be done. FIG. 10 shows an example of such a molecular network expansion operation.

 Biological events related to the molecular network may be added to the graph of the molecular network as vertices. In this case, it is preferable to display the biological event using a symbol different from the molecule. For example, a biological event caused by the establishment of a relationship between molecules (ie, the formation of a molecule pair).

Regarding (hereinafter referred to as a downstream biological event), an arrow may be drawn from the molecule pair (or any molecule of the molecule pair) toward the downstream biological event. When a certain biological event occurs and a relationship between certain molecules is established (that is, a molecule pair is formed), the biological event (hereinafter, referred to as an upstream biological event) is used to determine the relationship between the molecules. Draw an arrow toward the molecule pair (or any molecule of the molecule pair).

 The graph of the molecular network may be drawn by adding the path paths related to the molecules in the molecular network as vertices. In this case, it is preferable to display the pathway with a symbol different from the molecule. For example, when a certain molecule pair is formed and a certain pathway is activated, the molecule pair (or any molecule of the molecule pair) is converted to the pathway (hereinafter, referred to as “downstream pathway”). Draw an arrow toward. When a certain pair of molecules is formed by the operation of a certain path pair, the pair of molecules is directed from the above-mentioned pathway (hereinafter referred to as “upstream pathway”) to the above-mentioned molecule pair (or any molecule of the molecule pair). And insert an arrow.

In the case where a biological network and / or a pathway are added to a child network as described above, it is necessary to determine by calculation such that the symbols representing the molecule and the biological event and / or the pathway have an optimal arrangement that does not overlap. Good. FIG. 5 shows an example of a molecular network display including a biological event and a pathway thus drawn. With such a display, the user can easily understand the relationship between the molecular network in the molecular function network and the biological event and the z or pathway. In addition, similar to biological events, pathological events can be You may draw in addition to the h.

 As another embodiment of how to draw a graph of a molecular network, a molecular network that leads to a molecule that exists in common upstream or downstream of two or more molecules (hereinafter, referred to as a “common upstream molecule” and a “common downstream molecule”, respectively) is described. A method for marking and displaying a common upstream molecule or a common downstream molecule generated by a connect search is provided. Fig. 11 shows an example in which a molecular network from two molecules to a common upstream molecule is generated by a connect search, and the common upstream molecule is marked and displayed. As a method of marking, in addition to the method of attaching a symbol to the common upstream molecule or the common downstream molecule as shown in Fig. 11, a method of coloring those molecules or displaying them using different symbols can be used. it can.

 Search for common upstream molecules is performed in the upstream direction (the opposite direction of the arrow in Fig. 11) from each molecule specified as the starting point, taking into account the direction of the molecule pair such as signal transmission, enzyme reaction, and transcriptional control. And the connection search can be performed recursively or sequentially until the common molecule is found. The number of common upstream molecules is not limited to one, and two or more common upstream molecules may be found as shown in Fig. 11. The search for the common downstream molecule can be performed in exactly the same manner except that the direction of the molecule pair is considered in the opposite direction.

 By searching for and displaying a common upstream molecule, the user can easily know the molecule that commonly affects the abundance or state change of multiple molecules. By searching for and displaying common downstream molecules, users can easily find out which molecules are affected by multiple molecules in common and whose abundance or state changes. As described in PC TZ JP 03/028847, the connection search is not limited to molecules, but can be linked to any information items such as subnets, biological events, pathological events, drug molecules, genes, etc. It is needless to say that the search for common upstream molecules and common downstream molecules can also be performed using information items other than these molecules as starting points.

As still another embodiment of a method of drawing a graph of a molecular network, a connect search is performed again by specifying one or more molecules in a once generated molecular network, A method is provided for marking and displaying the generated molecular network (which is a partial network of the original molecular network). In the molecular network once generated in Fig. 12, a partial network connecting one molecule (indicated by * in the figure) as the starting point and two molecules (indicated by # in the figure) as the ending point Here is an example in which a is found by a connect search and marked (molecules belonging to partial networks are shown in reverse video). This display method has an effect when, for example, the expression of a certain protein is suppressed by a method such as knockout or RNA interference (RNAi), or when the function of a certain protein is altered by a transgenic (also called knock-in) method. This is useful for the purpose of predicting the range of the molecular network to be affected.

 The information window displays information on molecules, molecule pairs, and biological / pathological events included in the target molecular function network. The display format of the information is not particularly limited. For example, it is preferable to display the information in a tabular format for each category of information such as a molecule, a molecule pair, and a biological event (including a pathological event). In the following description, depending on the content of the information displayed in the information window, for example, “Molecular information window”,

Sometimes referred to as the "pathology information window."

 It may be convenient to group and / or organize information on bio-events based on their relevance. As an example of the layering of information on biological events, Gene Ontology and onsortium (http: // www. Geneontology. Org _; [the "Gene Ontology" described above.) As a preferred embodiment of the present invention, Biological events expressed in a hierarchy like Gene Ontology are displayed in an information window in a format such as a file format that allows users to easily understand the hierarchy, and data items and molecular network windows for each hierarchy are displayed. A graphical user interface is provided that allows the user to operate the items in conjunction with them.

In some cases, it is convenient to organize the information of pathological events into groups and / or hierarchies as well as biological events. Among the pathological events, an example of stratification of disease names is “International Classification of Diseases (ICD) J” by the World Health Organization (WHO). Stratification of pathological events including disease names and symptoms Examples include the International Federation of Pharmaceutical Manufacturers

MedDRA by Associations (IFPMA) and SNOMED by College of American Pathologists (CAP). As one of the preferred embodiments of the present invention, the information of the pathological events represented in a hierarchical manner is displayed in an information window in a format such as a file format that allows a user to easily grasp the hierarchical level. A graphical user interface is provided that enables data items in each layer to be operated in conjunction with items in the molecular network window. Quantify the strength of the relationship between the molecular network and information items such as pathways, biological events, pathological events, and drug molecules by an appropriate method, and calculate a numerical value or marker indicating the strength of the relationship for each information item. The display allows the user to more easily and appropriately understand the relationship between the information items.

 As an example of quantifying the strength of such a relationship, among the molecules displayed in the molecular network window, information items that can be associated with a certain information item (pathway, biological event, pathological event, drug molecule, etc.) Any method can be used), and the number of molecules associated with the number is counted, and the number (hereinafter referred to as the “number of associated molecules”) is used as an index value of the strength of the relationship.

 If the information of each association includes a weight indicating the strength of the relationship, the weights may be integrated when counting the number of molecules. Alternatively, the numerator may be calculated based on the weight. It may be determined whether or not to count. The number of associating molecules may be used as an index value, or alternatively, a ratio obtained by dividing the number of associating molecules by any of the following number of molecules may be used as an index value; The total number of display molecules in the database, or the number of molecules in the database of the present invention that are associated with the information item.

By displaying the index value of the strength of the relationship calculated in this way for each information item in the information window, the user can know how strong a certain information item and the displayed molecular network are. You can easily understand if you have a relationship. In addition to the method of displaying index values, a method of adding appropriate markers according to the index values, information items May be colored or highlighted.

 One of the features of the preferred embodiment of the present invention is that related items in the molecular network window and the information window can be operated in conjunction with each other. Specific examples will be described below, but it goes without saying that the scope of the present invention is not limited to the following examples. Example

 In the following examples, it is assumed that a “biomolecule information database”, a “biomolecule linkage database”, a “pharmaceutical molecule information database”, and a “pathology linkage database” are prepared. The biomolecule information database stores information on biomolecules. Examples of information to be stored include molecular abbreviations, synonyms, structure codes, function codes, species, producing organs, and existing organs. The biomolecule linkage database stores information on pairs of related biomolecules. Examples of information to be stored include the formal names and molecular abbreviations of the two molecules that make up the pair, the conditions under which the relationship is established, and information on biological events that occur with the relationship.

 The “pharmaceutical molecule information database” stores information on drug molecules. Examples of information to be stored include names of drug molecules, molecular abbreviations, applicable diseases, target biomolecules, and the like. The “pathology database” stores information on diseases. Examples of information to be stored include the name of the disease, key molecules that change quantitatively or qualitatively in the disease, pathological events, symptoms / symptoms, complications, disease classification, and laboratory test items. It is desirable to store not only the items in each of these categories, but also information on the M department between items belonging to different categories.

The methods for configuring the various databases described above and the method for generating a molecular function network using those databases are described in PCT / JP01Z07830 / specified document or PCTZ JP03 / 02284. The method described in the specification of No. 7 can be used. Example 1

 Fig. 1 shows an example in which the molecule items in the molecule network window and the information window are linked and displayed. First, the system generates an appropriate range of molecular function networks according to the user's specifications. The molecular network window displays the molecular network according to the above method. Next, when the user clicks on any vertex (corresponding to a molecule) or an edge (corresponding to the relationship between a molecule and a molecule) in the molecular network window, the system uses the relevant molecule as a query to query the molecular information data. Search the database and display the obtained molecular information in the information window. In Fig. 1, molecular information is divided into different columns for each category and displayed in the information window at the lower right of the screen for easy viewing by the user. With this display method, the user can easily browse information on any molecule in the molecule network.

 When the side is clicked above, the molecular information database is searched for each of the molecules at both ends of the side, and the search results are merged and displayed in the information window. Furthermore, by searching the vicinity of the clicked vertex or edge based on the topology of the molecular network, a list of molecules within a certain range is topologically obtained, and then the molecular information database is searched for each molecule in the list. To merge the search results and display them in the information window. Fig. 1 shows an example in which a molecule within one pass from the clicked molecule (IL-1) is displayed in the information window at the lower right of the screen. With this display method, users can easily browse information about molecules around any molecule in the molecule network.

By highlighting the molecule or side clicked by the user by changing the color or drawing line width in the molecular network window, the user can compare the clicked molecule or side with the display content in the information window. Makes associations easier to understand. In addition, when a clicked molecule or a molecule around a side is searched based on the topology, not only the tallyed molecule but also the surrounding molecules are highlighted as shown in the molecule network display in the upper right of FIG. Should be displayed. The search of the molecular information database of the present embodiment may be performed for all the entries of the database, but a subset of the molecular information database including only the molecules included in the molecular function network is extracted at the time of generating the molecular function network. By making the subset a search target, it is possible to perform the processing at higher speed.

 Furthermore, using the above subset of the molecular information database, simultaneously with the display of the molecular network in the molecular network window, information on all the molecules included in the molecular network may be displayed in the molecular information window. In this case, when the user clicks on a vertex or a side in the molecule network window, a search for molecular information is performed in the same manner as described above, and information on the corresponding molecule in the information window may be highlighted. The highlighting allows the user to easily view information about any molecule in the molecule network, or, conversely, if the user clicks on an item in the molecule information window, It is advisable to highlight the corresponding molecule of Example 2. Example 2

 Fig. 6 shows an example in which the items of the molecule pairs in the molecule network window and the information window are linked and displayed. First, the system creates an appropriate range of molecular function networks according to the user's specifications. The molecular network window displays the molecular network according to the above method. Next, when the user clicks on an arbitrary edge (corresponding to the relationship between molecules and molecules) in the molecular network window, the system searches the molecular chain database for a pair of molecules consisting of the molecules at both ends of the edge, and searches for the relevant pair. Information about the molecule pair to be displayed is displayed in the information window.

If the user clicks on any molecule in the 'Molecule Network' window, the system searches the molecular chain database for a molecule pair containing either of the molecules and displays information on the molecule pair in the information window. I do. In addition, when the user searches for a molecule that is tallic or a molecule around a side based on the topology according to the method of the first embodiment, the system finds a molecule pair including the peripheral molecule in a molecular chain data. Search from the database and display information on the corresponding molecule pair in the information window.

 The emphasis display of the molecule or the side clicked in the molecular network window of the first embodiment can be used also in the present embodiment. The highlighting allows the user to more easily understand the relationship between the clicked molecule or edge and the content displayed in the molecule pair information window. In the example shown in Fig. 6, information on the molecule pair between IL-1 and the molecule within one pass from the molecule IL-1 clicked by the user ("Molecular relation information" is added in the figure) Is displayed in the lower right information window.

 Although the search of the molecular chain database of the present embodiment may be performed for all the entries of the database, when the molecular function network is generated, a subset of the molecular chain database including only the molecules included in the network is extracted. By making the subset a search target, it is possible to perform the processing at higher speed.

 Further, using the above subset of the molecular chain database, the information of all the molecule pairs included in the molecule network may be displayed in the molecule pair information window simultaneously with the display of the molecule network in the molecule network window. In this case, when the user clicks on a vertex or an edge in the molecule network window, the molecule pair is searched in the same manner as described above, and the information of the corresponding molecule pair in the information window may be highlighted. This highlighting allows the user to easily view information about any molecule pair in the molecule network. Conversely, if the user clicks on an item in the molecule pair information window, the corresponding side in the molecule network window should be highlighted. Example 3

Fig. 7 shows an example in which the pathological event items in the molecular network window and the information window are linked and displayed. In the display of the molecular network in the upper right, the key molecules that are quantitatively or qualitatively changed in the disease are highlighted in black and white based on the information on the key molecules in the disease state chain database (IL-1, Molecules such as NFkB and PPARg). When a user clicks on IL-1, one of the key molecules, on the molecular network display, the system associates the key molecule (ie, IL-1) with information based on the information in the pathology database. Diseases with rheumatoid arthritis (underlined “rheumatoid arthritis”) are highlighted in the summary information window on the left. At the same time, the system extracts information about the disease from the disease state chain database and displays each item in the detailed information window at the lower right. At this time, all information related to the disease may be displayed, but if only items related to the clicked key molecule are displayed, it is convenient to grasp the relationship between the key molecule and each information item. It is. Fig. 7 shows an example in which only items related to IL-1 are displayed. For example, IL-1 which is a key molecule (indicated as “mediate molecule” in the figure) is expressed in “C0X-2 expression (synovium) Cell) ”and a symptom such as“ synovitis ”. Example 4

 Fig. 8 shows an example of linked display of drug molecule information items in the molecular network window and the information window. In the display of the molecular network in the upper right, the biomolecules that are the targets of the action of drug molecules are highlighted in black and white based on the information on the target biomolecules in the drug molecule information database (molecules such as ALDR and HK).

When a user clicks on one of the target biomolecules, ALDR, on the molecular network, the system uses the information in the drug molecule information database to target the drug (ie, ALDR) that targets the target molecule (ie, ALDR). Underlined “epalr _e stat”) is highlighted in the summary information window on the left. At the same time, the system extracts information on the drug molecule from the drug molecule information database and displays each item in the detailed information window at the lower right. Example 5

Fig. 13 shows an example of a graphical user interface that operates by linking hierarchically expressed information on pathological events and molecular networks. system Displays hierarchically the information of disease names among the pathological events in the information window on the left. In this window, if the user, for example, clicks on the item “Ischemic heart disease / angina pectoris spasm”, the system searches for the key molecule corresponding to the disease name based on the information in the pathology database, Among the key molecules, highlight the TXA2 molecule contained in the upper right molecular network window.

 At the same time, the system displays a list of key molecules corresponding to the disease name in the lower right information window. The type of change (+ indicates increase or activation) of the TXA2 molecule in the disease and the change The information of pathological events related to is displayed hierarchically. The causal relationship between the key molecule transformation and the pathological event is indicated by a right or left arrow. In this way, by making it possible to operate the information of the pathological event and the molecular network linked to each other in a stratified manner, the user can easily associate the information of the pathological event with the molecules in the molecular network. Can read and understand. Example 6

Fig. 14 shows an example of a graphical user interface that operates by linking information of Gene Ontology, which is a kind of hierarchical expression of biological events, and molecular networks. The system displays Gene Ontology information hierarchically in the left information window. In this window, when the user, for example, clicks on the item "prostanoid biosynthesis", the system searches for the molecule corresponding to the item based on the information in the biomolecule linkage database, and among those molecules, the upper right corner is displayed. Enhance the molecules (COX, C0X-1, COX-2, L-PGDS, PGIS) contained in the molecular network window. At the same time, the system displays the biological event (Gene Ontology item) in the lower right information window. Display detailed information about Here, detailed information is displayed not only for the item clicked by the user (prostanoid biosynthesis), but also for items registered in the lower hierarchy of Gene Ontology. In this way, it is possible to operate the information of biological events hierarchically represented and the molecular network in conjunction with each other. Thus, the user can easily browse and understand the relationship between the information of the biological event and the molecules in the molecular network.

 In this embodiment, the strength of the relationship between each item of the biological event and the displayed molecular network is indicated by a small black dot on the left side of each item of the biological event. For example, to the left of the item "prostanoid biosynthesis", two and three black dots are displayed vertically. Among them, the number of black dots in the left column indicates the ratio of molecules related to the biological event among the molecules in the molecular network, and the number of black dots in the right column indicates the total number of molecules related to the biological event. It represents the ratio of the molecules displayed in the molecule network among the molecules. The number of black spots is adjusted and displayed according to the value of the ratio. Industrial applicability

 By the method and the graphical user interface of the present invention, various biological information such as biomolecules, bio-events, pathological events, drug molecules, and genes can be easily browsed by linking them to a molecular function network. . FIG. 15 shows the concept of the connection between the molecular network and various biological information and related information that can be handled by the method of the present invention and the graphic camera user interface.

Claims

The scope of the claims 1. A graphical user interface that generates an arbitrary range of molecular function networks according to the user's instructions and displays the molecular function networks graphically.  2. A molecular network window displaying a molecular network included in the molecular function network, and one or more information selected from the group consisting of molecules, molecule pairs, and biological events included in the molecular function network are displayed. A graphical user interface comprising an information window, wherein the molecular network window and items related to each other in the information window are operated in conjunction with each other. 3. Molecular pairs in the molecular network window and the biological events that occur due to the quantitative and / or qualitative variation of the molecular pair or that cause the quantitative and / or qualitative variation of the molecular pair A graphical user interface for displaying information in association with each other and operating the displayed items in conjunction with each other.  4. Information about the molecules in the molecular network window and the biological events that occur due to the quantitative and / or qualitative changes in the molecule or that cause the quantitative and / or qualitative changes in the molecule. A graphical user interface, wherein the graphical user interface displays the items in association with each other and operates the displayed items in conjunction with each other.  5. A graphical user interface characterized by displaying a molecule in a molecule network window and information on a drug / bioactive molecule acting on the molecule in association with each other, and operating the displayed items in conjunction with each other.  6. A graphical user interface comprising a window for displaying a list of molecules in a molecule network window, wherein the molecules in the molecule network are operated in conjunction with the items in the list window. 7. Provide a window that displays a list of information on molecules and / or molecule pairs in the molecule network window, and operate the molecules and / or molecule pairs in the molecule network in conjunction with the items in the list window. Graphica characterized by Nore user interface.  8. A window is provided for displaying a list of biological pathways to which the molecules and / or molecule pairs in the molecule network window belong, and the molecules and / or molecule pairs in the molecule network and the items in the list window are displayed. Graphical user interface characterized by interlocking operations.  9. A window for displaying a list of information on biological events related to the molecules and / or molecule pairs in the molecule network window is provided, and the molecules and / or molecule pairs in the molecule network and the items in the list window are displayed. Is a graphical user interface that operates in conjunction with  10. A graphic camera user interface comprising a window for displaying a list of information on pathological events, and operating items related to each other in the list window in an interlocked manner.  11. The graphical user interface according to claim 10, wherein pathological events are displayed by category.  12. The graphical user according to claim 10, comprising a list of information relating to quantitative and / or qualitative changes in biomolecules associated with the pathological event.  13 3. A graphical user interface characterized by performing a keyword search on molecular function network information and highlighting the hit items in the search in the molecular network window and the related list window. Source.  14. Select one or more molecules and / or molecule pairs in the molecule network window, specify the molecules and / or molecule pairs as end points, and generate and display a molecular function network by connect search. Graphical user interface. 15. A molecular function, characterized by distinguishing molecules and Z or molecule pairs by symbols and / or color types based on information on modification state and Z or activation state. How to display the network.  16. A method for displaying a molecular function network, wherein a molecule and / or a molecule pair is distinguished and displayed according to a symbol and / or a color type based on information of a biological event.  17. Display of a molecular function network characterized by distinguishing and displaying molecules and / or molecule pairs based on information on biomolecules to be acted on by bioactive molecules based on the type of symbol and / or color. Method.  18. Characteristically, molecules and / or molecular pairs are distinguished and displayed by symbol, Z or color type based on numerical information indicating the quantitative and / or qualitative state of molecules and / or Z or molecular pairs. To display the molecular function network.  1 9. A method for displaying a molecular function network, characterized in that the sides connecting the molecule pairs are distinguished and displayed by a drawing method based on the association information of the molecule pairs.  When displaying a complex consisting of two or more biomolecules, it is possible to switch between displaying a single symbol representing the complex or displaying multiple symbols representing each constituent molecule. A method for displaying a molecular function network characterized by the following. 21. A biological event related to a molecule and / or a molecule pair in a molecular network is displayed as a vertex, and the molecule and / or the molecule pair and the vertex are connected by an edge to be displayed. Display method of molecular function network.  22. A bioactive molecule that targets a molecule and / or a molecule pair in a molecular network as an action target is displayed as a vertex, and the molecule and / or molecule pair and the vertex are connected by an edge to be displayed. How to display the characteristic molecular function network.  23. Display the biological pathway and / or other molecular network related to the molecule and Z or the molecule pair in the molecule network as a vertex, and connect an edge between the molecule and / or molecule pair and the vertex. A method for displaying a molecular function network, characterized in that the method is displayed by using. 24. A display screen for a molecular function network that executes the graphical user interface or the display method according to any one of claims 1 to 14. Program.  25. A display program for a molecular function network, which executes the display method according to any one of claims 15 to 23.  26. A computer-readable medium on which the program according to claim 24 or 25 is recorded. -27. A display device for a molecular function network capable of executing the program according to claim 26.